Efficacy and safety of caffeic acid tablets in the treatment of thrombocytopenia: A systematic review and meta-analysis

Background: Caffeic acid tablets (CFA) are a proprietary Chinese medicine in treating thrombocytopenia. The efficacy and safety of CFA compared with other platelet-raising drugs for the treatment of thrombocytopenia have been widely reported in the literature, but there is no systematic evaluation. Therefore, we designed this meta-analysis to further establish the efficacy and safety of CFA in treating thrombocytopenia. Methods: A computerized search was conducted in the Chinese biomedical database (CBM), Chinese National Knowledge Infrastructure (CNKI), Wanfang database, Chinese Scientific Journal Database (VIP), PubMed, and Web of Science databases using the keywords “caffeic acid tablets” and “thrombocytopenia.” All randomized controlled trials were selected for the timeframe of build to 02/2023 and then screened and analyzed using RevMan 5.4 and stata17.0 software. Results: A total of 35 publications with an overall 2533 patients were included in the study. The results of the meta-analysis showed that CFA were effective in the treatment of thrombocytopenia with a statistically significant difference [relative risk ratio (RR) = 1.24, 95% CI (1.17, 1.31), P < .00001] and in increasing platelet counts [standardized mean difference (SMD) = 1.50, 95% CI (1.09, 1.91), P < .00001], white blood cell count [SMD = 1.08, 95% CI (0.77, 1.39), P < .00001], and neutrophil count [SMD = 0.73, 95% CI (0.19, 1.28), P = .009], and CFA reduced myelosuppression [RR = 0.19, 95% CI (0.1, 0.37), P < .00001] and adverse effects [RR = 0.75, 95% CI (0.58, 0.96), P = .02]. Conclusion: CFA can effectively improve the clinical outcome of patients with thrombocytopenia with a good safety profile and are worth promoting. However, due to the low quality and small sample size of the included literature, a larger sample size and more standardized, high-quality studies are needed to validate these results.


Introduction
Platelets are derived from megakaryocytes, and their production and maturation in the bone marrow is regulated by thrombopoietin. [1]Platelets play an important role not only in thrombosis and wound repair, but also in inflammation, immunity and cancer biology. [2]Thrombocytopenia refers to a platelet count (PLT) <100 × 10 9 /L.The main pathogenesis of thrombocytopenia is a decrease in platelet production, increased destruction and accumulation in the spleen, usually due to bacterial or viral infections, liver diseases, hematologic diseases, malignant tumors, pregnancy, autoimmune diseases, thrombotic microangiopathy, etc. [3] Thrombocytopenia is a common problem that affects 40% to 50% of medical and surgical intensive care units. [4]For thrombocytopenia caused by immune thrombocytopenic purpura (ITP), the main first-line treatment is glucocorticosteroids, immunoglobulins, etc. [5][6][7] Second-line treatment strategies include thrombopoietin receptor agonists; however, these agents often fail to achieve durable remission and require additional treatment options. [8]For chemoradiotherapy-induced thrombocytopenia, treatment includes platelet transfusions and administration of platelet growth factors, but the side effects are numerous and expensive. [9]he main ingredient of caffeic acid tablets (CFA) is caffeic acid (CA).CA is a hydroxycinnamic acid that belongs to the phenolic acid family of polyphenols.And also known as "3,4-hydroxycinnamic acid" or "3,4-dihydroxy phenyl acrylic acid." [10][28] Besides these important activities, CA and its derivatives have shown a very high potential for treating and preventing cardiovascular and cancer diseases in preclinical studies. [10,29]In addition, CA also has the effects of hemostasis, raising white blood cells and platelets, and is clinically used in the treatment of leukopenia and thrombocytopenia caused by various reasons. [30]he efficacy and safety of CFA compared with other platelet-raising drugs in the treatment of thrombocytopenia have been widely reported in the literature, but there is no systematic evaluation, so this study used meta-analysis to compare the efficacy and safety of CFA with other platelet-raising drugs in the treatment of thrombocytopenia, with the aim of providing a reliable basis for clinical use and evidence-based guidelines.

Ethical approval and consent to participate
The PRISMA guidelines [31] were used for designing and reporting this study, and this study was in accordance with the ethical guidelines of the Declaration of Helsinki (as revised in 2013). [32]This study is a systematic evaluation type article and does not require ethical approval.

Inclusion criteria
Research type: Only randomized controlled trials were included and the languages were limited to Chinese and English.
Research object: The included study cases were all patients with a diagnosis of thrombocytopenia.Refer to Consensus on the clinical diagnosis, treatment, and prevention of chemotherapy-induced thrombocytopenia in China (2019 version), [9] Thrombocytopenia is classified as degree I-IV, degree I:

Exclusion criteria
Have any serious medical condition such as heart, brain, and kidney injury; no studies of any of the outcome indicators included in this study or literature not available in full; no control group or self-control; cohort studies, animal studies, clinical experience, etc.; and conference articles.

Literature screening and data extraction
The literature was screened and cross-checked by 2 investigators independently and in case of disagreement, both parties negotiated and requested a ruling from a third investigator.
Information extracted from the literature included the first author, year of publication, type of disease, number of patients, mean age, interventions, outcome indicators, and duration of treatment.

Literature quality assessment
The quality of the included literature was evaluated using the risk of bias assessment tool recommended in the Cochrane Systematic Evaluator Handbook 5.1.0.This specifically included random sequence generation, allocation concealment, blinding, completeness of outcome data, and other sources of bias.Each item was categorized into content rated as high risk, unclear and low risk. [33]

Statistical methods
Meta-analysis was performed using RevMan 5.3 and Stata 17.0 software.Count data were analyzed by relative risk ratio (RR), and continuous data were analyzed by mean difference (MD) or standardized mean difference (SMD).Also, their combined effect sizes and their 95% confidence intervals (CI) were calculated.Heterogeneity was analyzed using the Q test and I2 test. [34]If there was no statistical heterogeneity between studies (I2 < 50%, P > .10), a fixed-effects model was used for analysis, otherwise, a random-effects model was used.The same outcome indicators were analyzed in subgroups according to disease type, treatment regimen, and the duration of treatment.Sensitivity analysis was performed using Stata 17.0 software.The publication bias analysis was performed using inverted funnel plots.P < .05 was considered statistically significant.

Basic characteristics of the included literature
The basic information of the literature included were shown in Table 1. [20]Most of the patients were cancer patients with the youngest participant being 7 years old and the oldest being 62 years old.The shortest duration of treatment in the study was 2 weeks and the longest was 12 weeks.

Risk of bias assessment for inclusion in the literature
All included trials were found to have a high risk of bias due to inadequate or insufficient reporting of information on study design and methods.][48]57] described the use of visit order to generate random assignment and were therefore assessed as having a high risk of bias.Since CFA were only used in the trial group, it seems unlikely that any of the trials blinded participants and staff, except for Majun 2017 [53] which used double blinding.Information on allocation concealment and blinding of outcome assessment was not reported in any of the trials and was therefore judged as unclear.Withdrawal information was not reported in any of the trials and was therefore assessed as unclear.As none of the trials provided information on trial registration, we assessed reporting bias by judging the consistency between results in the methods section of the publication, and 2 of the trials [40,54] were assessed to be at high risk of selective reporting bias because it had apparent problems with primary outcome reporting. The remainin trials were assessed as having a low risk of selective reporting bias due to studies reporting all outcomes mentioned in the methods section.Other bias was assessed by comparability of baseline data between the 2 groups, with 2 [51,62] trials reporting baseline data, including age and sex, with no statistical description of comparability, and therefore they were assessed as having an unclear risk of bias.See Figures 2 and 3 for details.
The results of the subgroup analysis are detailed in Table 2. based on these results, it can be demonstrated that the source of heterogeneity may be related to the type of disease, but may not be related to the treatment regimen or the duration of treatment of the disease.Based on the changes in platelet counts, funnel plots were drawn using stata17.0software with the standard error SE (SMD) of the effect size as the vertical coordinate and the SMD of the effect size for each study as the horizontal coordinate in Figure 5, which showed that the funnel plots were less symmetrical on both sides and there was a significant publication bias.

White blood cell count analysis.
Thirteen studies [38,39,42,44,47,49,54,55,58,59,61,66,68] reported changes in leukocyte counts before and after treatment.Meta-analysis results showed high heterogeneity (P < .00001,I 2 = 80%) between study groups, so random-effects model analysis was used.Metaanalysis showed that compared with the control group CFA group significantly improved PLT with a statistically significant difference [SMD = 1.08, 95% CI (0.77, 1.39), P < .00001]as detailed in Figure 8. considering the high heterogeneity, subgroup analysis was performed according to disease type, treatment regimen and duration of treatment.The results of the subgroup analysis are detailed in Table 3.Based on these results, it can be demonstrated that the source of heterogeneity may be related to the type of disease, but may not be related to the treatment regimen or the duration of treatment of the disease.Based on the changes in leukocyte counts, funnel plots were drawn using stata17.0software with the standard error SE (SMD) of effect sizes as the vertical coordinate and the SMD of effect sizes for each study as the horizontal coordinate in Figure 9, which showed that the funnel plots were less symmetrical on both sides and that there was publication bias.

Myelosuppression rate at degrees III and IV.
Four studies [38,39,59,66] reported III and IV degrees of myelosuppression, and the meta-analysis showed that the CFA group may reduce the occurrence of myelosuppression compared to the control group [RR = 0.19, 95% CI (0.1, 0.37), P < .00001],heterogeneity (P = .68,I 2 = 0%), so a fixed-effect model analysis, as in Figure 11.
3.4.6.The incidence of adverse reactions.Adverse reactions were reported in 12 studies [38][39][40]43,44,49,54,55,59,60,66,68] and the details of the included adverse reactions are shown in Table 4, while the others did not report the specifics of the adverse reactions. These results suggest that FA have no or mostly mild adverse reactions in patients.
3.4.7.Sensitivity analysis.Sensitivity analysis of the included studies has shown no significant differences between the random-effects model and fixed-effects model.The exclusion of any of the studies had little effect on the results indicating low sensitivity and strong confidence in the results.

Discussion
Thrombocytopenia, usually defined as a PLT of < 100 × 10 9 /L in peripheral blood, is a common complication in oncology patients. [70]However, ITP can also present with symptoms of thrombocytopenia.ITP is a hemorrhagic disease characterized by an increase in platelet destruction due to the production of anti-auto-platelet antibodies in the patient body, resulting in a persistent reduction of platelets in the peripheral blood and a normal or increased number of bone marrow megakaryocytes with maturation disorders, and it is the most common type of thrombocytopenic disease in the clinic. [71]Thrombocytopenia may increase a patient risk of bleeding, thereby endangering the patient life and health, as well as affecting treatment outcomes and increasing medical costs. [72]Thrombocytopenia is mostly treated with glucocorticoids, splenectomy and immunomodulators vincristine, cyclophosphamide and rituximab in western medicine, which have greater adverse effects.Adverse effects of glucocorticoids include osteoporosis and even aseptic femoral head necrosis, water and sodium retention, centripetal obesity, acne and elevated blood pressure and blood glucose, which have a high incidence and seriously affect the quality of life of patients. [63]FA are rapidly absorbed after oral administration and have a high distribution in the blood and kidneys.The mechanism of action of CFA is complex and varied [73,74] , Ferulic acid and isoferulic acid are the 2 main bioactive metabolites of caffeic acid.The t 1/2 of caffeic acid was 1.25 ± 0.26 hours.The reason for the difference in t 1/2 of caffeic acid in different pathways may be the rapid transfer from blood to tissue.Its absolute bioavailability was 3.4%, suggesting that caffeic acid may have a rapid biotransformation in vivo, with poor permeability through the intestinal epithelial membrane. [75]Caffeic acid also stimulates the differentiation of hematopoietic stem cells, the proliferation of endothelial cells and the expression of surface adhesion molecules, thus improving the hematopoietic function of the body.It also increases the synthesis of deoxyribonucleic acid in leukocytes, stimulates the synthesis of megakaryocyte proteins and antioxidants, which contribute to anti-apoptosis, regulates the function of T cells and reduces the destruction of peripheral blood cells, thus increasing the level of platelets and leukocytes. [65]Caffeic acid also improves microvascular and platelet function and coagulation factors by reducing the time to coagulation and hemostasis. [76]In patients with thrombocytopenia and leukopenia, caffeic acid has been found to have a rapid onset of action and precise efficacy. [77,78]n this study, 35 papers were included through a search of relevant domestic and international literature, and the results of a clinical randomized controlled study comparing the CFA group with the non-CFA group by meta-analysis showed that the difference between the CFA group and the control group was statistically significant.From a clinical perspective, CFA did increase platelet counts and improve patient health.In addition, there were few serious adverse events and treatment-related safety issues, and our subgroup analysis of 2 outcome indicators, PLT and white blood cell count, showed that the classification of the disease may be of heterogeneous origin.The results of this study showed that the application of CFA for the treatment of thrombocytopenia does have good clinical efficacy, and that CFA are safe and effective, have mild adverse effects, are inexpensive and easy to use, and are clinically worth promoting.From the results of the funnel plot, it can be seen that there may be publication bias in the meta-analysis, and from the sensitivity analysis showed that the sensitivity analysis of each index was consistent with the original results, with good stability and high confidence of the conclusion.
Our study still has some limitations.Firstly, the included articles were all Chinese studies with geographical limitations.Secondly, the sample size of each study was mostly from 1 hospital, which is a small sample size that may affect the reliability and accuracy of the findings.Furthermore, only 12 of the 35 papers reported a specific randomization method, and 4 of them were high-risk biased.Since some of the original studies were published too early, many did not report the use of allocation concealment and blinding and therefore their quality was not high.However, the aim of this study was to investigate the effect of CFA on thrombocytopenia.We chose objective results from clinical trials, such as PLT, white blood cell count, and neutrophil count, which were minimally affected by allocation concealment and blinding.Second, the heterogeneity between studies cannot be ignored because of the different interventions, drug doses, and treatment durations used in patients with different platelet levels in each trial.In our study, we performed a subgroup analysis to reduce heterogeneity to some extent.Finally, for adverse events, there were no clear conclusions about adverse effects of CFA due to the limited follow-up time of the included studies and the non-standardized reporting of some studies.

Conclusion
The results of this study showed that CFA are effective, safe and economical in the treatment of thrombocytopenia and are worthy of clinical application.However, due to the limitations of the quality of the included literature, sample size and study design, the above findings need to be validated by further large sample and high-quality clinical studies in the future.

Figure 3 .
Figure 3. Risk of bias bar chart.

Figure 11 .
Figure 11.Meta-analysis of grade III and IV myelosuppression.

Table 1
Basic information of included studies.

Table 2
Platelet count subgroup analysis.

Table 3
Leukocyte count subgroup analysis.